Overactive bladder refers to a clinical condition complaining urinary urgency regardless of incontinence, which is usually accompanied by urinary frequency and nocturia (Non-Patent Document 1). Currently, an anticholinergic agent is mainly used for the treatment thereof, and certain therapeutic outcome has been shown. However, it is known to cause side-effects such as dry mouth, constipation and blurred vision and it has been reported that the anticholinergic agent is difficult to be used for patients with prostatic hypertrophy or elderly patients because of a risk of urinary retention. In addition, there are patients showing no improvement with the anticholinergic agent. From the above facts, there is a great expectation for a drug with new mechanism of action against overactive bladder.
Nerve Growth Factor (NGF) is one of humoral factors named generically as a neurotrophic factor, which plays an important role in the development, differentiation and function maintenance of neurons in an organism. As the receptor of NGF, the high-affinity trkA receptor (receptor tyrosine kinase) and the low-affinity p75 receptor have been known. It has been reported that p75 binds to all of nerve growth factors, and is involved in apoptosis in the process of neuron development, but its role has not yet been fully elucidated. It has been known that NGF and trkA receptor-knockout mice show the same phenotype (Non-Patent Document 1), and it is believed that a physiological action of NGF is exhibited mainly through the trkA receptor.
It has been known that the NGF level in bladder is high in a patient with overactive bladder or interstitial cystitis (Non-Patent Document 2), and it has been reported that an intravesical instillation of NGF reduces a bladder capacity of rat and that an inhibition of NGF improves urinary functions in the urinary frequency model rat (Non-Patent Document 3). In addition, there have been reported that the inhibition of NGF improved urinary frequency or incontinence in patients with interstitial cystitis (Non-Patent Document 4), and thus it is believed that a trkA receptor inhibitor is useful as an agent for treating urinary frequency/urinary urgency, and urinary incontinence which are associated with overactive bladder, and lower urinary tract diseases such as interstitial cystitis and prostatitis.
Moreover, a trkA receptor inhibitor has a different mechanism of action, and thus side effects which are characteristic to the anticholinergic agent are expected to be avoided and also an effect on patients who showed no improvement with the anticholinergic agent is expected. In addition, this agent is expected to show more potent effects on subjective symptoms by acting on sensory nerves. Furthermore, this agent has been reported to exhibit an effect of improving morbid conditions without lowering the urinary pressure in the urinary frequency model rat (Non-Patent Document 5), and thus it is expected that this agent can be administered safely to a patient with prostatic hypertrophy or an elderly patient.
It has been also known that administration of NGF to human or rat induces pain, and that algesthesia in the trkA knockout mice is lost. Consequently, NGF is believed to be strongly related in expression of pain. An NGF inhibition shows efficacy to the model animals with neuropathic pain or inflammatory pain, such as a model with pain induced by injury to sciatic nerve (Non-Patent Document 6) and a model with pain induced by damage to knee joint (Non-Patent Document 7), and the trkA receptor inhibitor is believed to be useful as an agent for treating a lower urinary tract disease accompanied by lower urinary tract pain and various kinds of pains such as an osteoarthritis.
As the compound mentioned above, there have been known an indolocarbazole derivative (Non-Patent Document 8), a pyrrolocarbazole derivative (Patent Document 1), a pyrazolone derivative (Patent Document 2), an oxyindole derivative (Patent Document 3 and 4), an azaoxyindole derivative (Patent Document 5), a pyrazolyl condensed ring compound (Patent Document 6), a pyrazole derivative (Patent Document 7 and 8), a tricyclic derivative (Patent Document 9) and ALE-0540 (Patent Document 10).
In addition to the above Non-Patent Document 8 and Patent Documents 1 to 10, as the compound having relatively similar structure, a compound represented by the following general formula (XV) is disclosed as a c-fms kinase inhibitor in Patent Document 11. However, a trkA receptor-inhibitory activity in the present invention is not mentioned at all. Furthermore, in this publication, there is no specific disclosure in Examples and so forth as for the compound having thiazole or oxazole skeleton wherein 2-position is substituted.

(In the formula, A is phenyl, naphthyl, or biphenyl which may respectively be substituted; or a 5 to 7-membered aromatic monoheterocyclic group or a 8 to 10-membered aromatic biheterocyclic group which may respectively be substituted and have 1 to 4 N, O, or S; R1 is —H, aryl, or the like; X is —CO—, —C(═NH)—, —CS—, or the like; R2 and R3 are each independently —H, C1-6 alkyl, aryl, cycloalkyl, or the like, while R2 and R3 may, together with the nitrogen to which R2 and R3 are bonded, form a 5 to 7-membered heterocyclic group or aromatic heterocyclic group, and the heterocyclic group may be substituted and contain 1 to 3 N, O or S; W is phenyl, naphthyl or biphenyl which may respectively be substituted, or a 5 or 6-membered monocyclic or 8 to 10-membered bicyclic heterocyclic group or aromatic heterocyclic ring, which may respectively be substituted and contain 1 to 4 N, O or S. For details, refer to the publication).    Non-Patent Document 1: ‘Reviews in the Neurosciences’, (England), 1997, vol 8, p. 13 to 27    Non-Patent Document 2: ‘British Journal of Urology’, (England), 1997, vol 79, p. 572 to 7    Non-Patent Document 3: ‘Neuroscience’, (U.S.A.), 1997, vol. 78, No. 2, p. 449 to 59    Non-Patent Document 4: ‘General Outline preliminarily described for the 99th American Urology Association’, (San Francisco), 2004, #363    Non-Patent Document 5: ‘The Journal of Urology’, (U.S.A.), 2005, vol 173, p. 1016 to 21    Non-Patent Document 6: ‘Pain’, (U.S.A.), 1999, vol 81, p. 245 to 55    Non-Patent Document 7: ‘Pain’, (U.S.A.), 2005, vol 116, p. 8 to 16    Non-Patent Document 8: ‘Cancer Research’, 1999, vol 59, p. 2395 to 2401    Patent Document 1: International Publication pamphlet WO01/14380    Patent Document 2: International Publication pamphlet WO01/32653    Patent Document 3: International Publication pamphlet WO02/20479    Patent Document 4: International Publication pamphlet WO02/20513    Patent Document 5: International Publication pamphlet WO03/027111    Patent Document 6: Japan Patent Application Publication 2003-231687    Patent Document 7: International Publication pamphlet WO2005/049033    Patent Document 8: International Publication pamphlet WO2005/103010    Patent Document 9: International Publication pamphlet WO2005/076695    Patent Document 10: International Publication pamphlet WO01/78698    Patent Document 11: International Publication pamphlet WO2004/096795